Cargando…

The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress

Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Suwei, Annesley, Sarah J., Jasim, Rasha A. F., Fisher, Paul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392454/
https://www.ncbi.nlm.nih.gov/pubmed/34440642
http://dx.doi.org/10.3390/cells10081874
_version_ 1783743507711655936
author Chen, Suwei
Annesley, Sarah J.
Jasim, Rasha A. F.
Fisher, Paul R.
author_facet Chen, Suwei
Annesley, Sarah J.
Jasim, Rasha A. F.
Fisher, Paul R.
author_sort Chen, Suwei
collection PubMed
description Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein’s ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity.
format Online
Article
Text
id pubmed-8392454
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83924542021-08-28 The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress Chen, Suwei Annesley, Sarah J. Jasim, Rasha A. F. Fisher, Paul R. Cells Article Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein’s ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity. MDPI 2021-07-23 /pmc/articles/PMC8392454/ /pubmed/34440642 http://dx.doi.org/10.3390/cells10081874 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Suwei
Annesley, Sarah J.
Jasim, Rasha A. F.
Fisher, Paul R.
The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title_full The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title_fullStr The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title_full_unstemmed The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title_short The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress
title_sort parkinson’s disease-associated protein dj-1 protects dictyostelium cells from ampk-dependent outcomes of oxidative stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392454/
https://www.ncbi.nlm.nih.gov/pubmed/34440642
http://dx.doi.org/10.3390/cells10081874
work_keys_str_mv AT chensuwei theparkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT annesleysarahj theparkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT jasimrashaaf theparkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT fisherpaulr theparkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT chensuwei parkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT annesleysarahj parkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT jasimrashaaf parkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress
AT fisherpaulr parkinsonsdiseaseassociatedproteindj1protectsdictyosteliumcellsfromampkdependentoutcomesofoxidativestress